Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson’s disease models

Autor: Jeremy M. Van Raamsdonk, Dylan J. Dues, Megan M. Senchuk, Jason F. Cooper, Emily Machiela, Katie K. Spielbauer
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: Scientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
Scientific Reports
ISSN: 2045-2322
DOI: 10.1038/s41598-017-16637-2
Popis: While the pathogenesis of Parkinson’s disease (PD) is incompletely understood, mitochondrial dysfunction is thought to play a crucial role in disease pathogenesis. Here, we examined the relationship between mitochondrial function and dopamine neuron dysfunction and death using C. elegans mutants for three mitochondria-related genes implicated in monogenic PD (pdr-1/PRKN, pink-1/PINK1 and djr-1.1/DJ-1). We found that pdr-1 and pink-1 mutants exhibit deficits in dopamine-dependent behaviors, but no loss of dopamine neurons, while djr-1.1 mutants showed an increased sensitivity to oxidative stress. In examining mitochondrial morphology and function, we found that djr-1.1 mutants exhibit increased mitochondrial fragmentation leading to decreased rate of oxidative phosphorylation and ATP levels. pdr-1 and pink-1 mutants show an accumulation of dysfunctional mitochondria with age, which leads to activation of the mitochondrial unfolded protein response (mitoUPR). Preventing the upregulation of the mitoUPR with a deletion in atfs-1 results in decreased lifespan and dopamine neuronal loss in pdr-1 and pink-1 mutants but not in wild-type worms. Overall, our results suggest that mutations in pdr-1 and pink-1 cause the accumulation of dysfunctional mitochondria, which activates the mitoUPR to mitigate the detrimental effect of these mutations on dopamine neuron survival.
Databáze: OpenAIRE
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